Abstract P222: Progesterone Induced Blocking Factor Decreases Hypertension, Mitochondrial Dysfunction And Reactive Oxygen Species In Response To Elevated Sflt-1 During Pregnancy

Abstract

Preeclampsia (PE) is characterized by new onset hypertension in association with placental ischemia, reduced fetal weight, elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and placental mitochondrial (mt) dysfunction and oxidative stress (ROS). Infusion of sFlt-1 causes hypertension and other characteristics of PE in pregnant rodents. However a role for sFlt-1 in causing mt dysfunction and ROS is unknown. Progesterone induced blocking factor (PIBF), is a product of progesterone signaling which lowers inflammatory processes. We have shown that PIBF lowers blood pressure in a rat models of PE. This study was designed not only examine the role of mt ROS in sFlt-1 induced hypertension during pregnancy but to also examine the effect of PIBF to improve mt function and hypertension in response to elevated sFlt-1 during pregnancy. sFlt-1 was infused into normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg –1 ·day –1 for 6 days, gestation days (GD) 13-19 ) in the presence or absence of PIBF (2.0 μg/mL) administered intraperitoneal on GD 15 to sFlt-1 induced hypertensive pregnant rats. Mean arterial blood pressure (MAP), placental and endothelial mt ROS and function were measured on GD 19. Infusion of sFlt-1 into NP rats increased MAP to 112 + 2 (n=11) compared with control NP rats 98 + 2 mmHg (n=15, p<0.05). Administration of PIBF reduced MAP to 100 + 1 mmHg in the presence of sFlt-1(n=5, p<0.05). Mt ROS in placenta was 108 + 6 in NP (n=4), 429 + 32 in NP+ sFlt-1(n=3) and reduced to 234 + 15 in NP+ sFlt-1+ PIBF (n=3). State 3 respiration, which is indicative of ATP production, was reduced in placentas of sFlt-1 infused rats versus NP, but was improved with PIBF. Moreover, sera from NP+sFlt-1 treated with PIBF attenuated endothelial cell mtROS ( 29 + 8 % gate) compared with sera from NP+sFlt-1 (54 + 15 % gate (n=4)). Our study indicates a role of sFlt-1 induced hypertension during pregnancy to reduce placental and endothelial cell mt function. Importantly, supplementation of PIBF improved mt function and ROS which was associated with improved blood pressure in sFlt-1 induced hypertensive pregnant rats indicating the efficacy of improved progesterone signaling as a potential therapeutic for PE.